The invention relates to the field of determining the presence and/or concentration of an analyte in a medium intended for sampling. Determination requirements of this kind occur particularly in the continuous or discontinuous monitoring of metabolic processes in a living entity such for example as a human being, in biotechnical cultivation and in other technical processes. What is desired in each of these cases is for the determination of the analyte, or in other words its presence and/or concentration in the medium being sampled, to be as prompt and as accurate as possible, without at the same time causing any interference with the medium intended for sampling or with the processes that may possibly be taking place in it and without any major amounts of the medium being consumed for the purposes of the analysis.
The invention will be described below chiefly in relation to applications to the bodies of human beings or animals, and in particular in relation to requirements in medical analysis. However, the invention is not limited to this field. Hence, where terms drawn from the medical field such for example as cannula or catheter are used, what these terms are also understood to mean, as further embodiments, are corresponding articles used in the chemical and biotechnology industries, such for example as tubes and flexible lines.
The determination of an analyte in a medium is usually performed by bringing a sensor suitable for the given analyte into direct contact with the medium intended for examination itself or with a sample of the medium that has been taken from the main body of the medium. In this way, in medical analysis for example, attempts are made to arrange miniaturized sensors directly in a patient and, when this is done, preferably in his blood stream. The given sensor is then intended to determine one or more assigned analytes continuously or at a preselected point in time, i.e. to ascertain its/their presence and/or concentration in the medium and to make the result of this ascertainment accessible in some suitable form, as an electrical signal for example or as a visual signal or a radio signal. It is a problem in this case that it is only with difficulty that a sensor arranged inside a patient, such for example as an implanted sensor or one situated in the blood stream, can be calibrated, because to do this a calibrating medium has to be introduced into the patient in such a way that it displaces any medium belonging to the body at the sensor's location to such an extent that any falsification of the calibration by effects coming from outside the calibrating medium can be largely or entirely ruled out. This is a very complicated process and because of the risk that it involves of an incursion into the patient it is impossible in many cases.
In medical analysis, attempts are therefore also made to obtain a sample of a medium from the patient, such as a blood sample for example, continuously or at a preselected point in time by fitting a sampling access to the patient. This sample is then conveyed to a sensor and is then discarded or fed back to the patient. It is particularly desirable for the sample to be fed back in order not to put the patient under unnecessary stress by the repeated taking of samples, in that this would, as it were, exsanguinate him. Hence, in the methods of analysis that have been described, the obtaining of a sample means that the sensor is no longer situated directly in the main body of the medium intended for analysis but in the sampling access, such as in a catheter or cannula for example, and analyses a sample of the medium that flows into, or that has flowed into, or that has been drawn by suction into, the sampling access. The sensor may equally well be arranged at an even greater distance from the main body of the medium, such for example as at an end of the sampling access remote from the main body of the medium. And finally, the sensor may even be totally separated from a fluid-carrying means of communication with the main body of the medium, such for example as by feeding a blood sample that has been isolated to an external sensor such as a test strip.
Where sensors are not arranged within the main body of the medium, it must be remembered that the characteristics of the medium intended for sampling may be altered simply by the taking of the sample from the main body of the medium. In this way, a blood sample for example that is drawn out quickly through a cannula may be subjected to high shear forces, which may result in damage-induced artifacts. Another cause for concern is that blood samples in particular clot. Clotting of this kind may for example take place even within a cannula or an indwelling venous catheter. This needs to be prevented not only to ensure that sensor signals are meaningful but also to stop thrombuses from being introduced into the patient.
In continuous-flow methods of medical analysis, it is often necessary for the sample intended for analysis to be left to stand in a measuring cell for a certain contact time, because flows and pulsations caused for example by the heart beat or by fluctuations in blood pressure may affect sensors.
Attempts have therefore been made to decouple the sensor and the medium intended for sampling from one another by interposing a transporting medium. In this case, the transporting medium is first brought into contact with the medium intended for analysis in order to charge the transporting medium with the analyte or analytes. The analyte-charged sample of the transporting medium is then transported to the sensor and measurements are made on it there. What is advantageous about methods of this kind is that by the interposing of a transporting medium it becomes possible for the conditions, such as pressure and temperature for example, prevailing at the sensor to be preselected and for them to be more accurately controlled than they can be in the medium intended for analysis. If the method is carried out in a suitable way, it is also possible to avoid any noticeable volume of material whatever being taken from the main body of the medium.
An example of methods of this kind is methods of dialysis. In them a probe is introduced into the medium to be examined and if necessary is implanted for a protracted period, the probe containing a transporting medium that, via a measuring window covered with a dialysis membrane or gas-diffusing membrane, is brought into metabolic communication with the medium intended for examination. The probe is flushed with the transporting medium continuously or in pulses. Through the membrane and the measuring window, the analyte enters the transporting medium in an analyte receiving chamber situated downstream of the membrane in the direction of flow of the analyte, and is transported out of the probe through a probe outlet and out of the region occupied by the medium to be examined, which region may in particular be a bioreactor or the body of a human or an animal. Examples of such probes and associated methods of sampling are described in DE 44 26 694, U.S. Pat. No. 3,640,269, U.S. Pat. No. 4,008,717, U.S. Pat. No. 4,221,567, U.S. Pat. No. 4,694,832, U.S. Pat. No. 6,632,315, U.S. Pat. No. 6,811,542, U.S. Pat. No. 6,852,500, U.S. Pat. No. 7,162,290, US 2008-97288, WO 99/45982 A2, WO 01/06928 A1, WO 2004/032735 A2, WO 2001/010483 A1 and WO 2008/059050 A2.
Precisely when the probe is arranged in the body of a living entity, and in particular in the body of a human or animal, the concentration of the analytes transported out of the probe may fluctuate widely in the transporting medium regardless of their concentration in the body of the living entity. The inventors suspect that the membrane closing off the measuring window comes into contact with tissue or other solid matter forming part of the living entity due to movements of the living entity and when this happens becomes partly or completely covered in such a way that passage of the analyte into the analyte receiving chamber is hampered. The inventors have also found that the concentration of the analyte in the transporting medium very much depends on the flow rate of the medium intended for analysis, and in particular on the flow rate of blood.
A further disadvantage is that, due to their small outside diameter, conventional microdialysis probes become awkwardly flexible as their length increases. Microdialysis probes need to be about 30 cm long to enable them to be inserted into, or rather through, the inner lumen of a central venous catheter. Long microdialysis probes of this kind are difficult to insert into a catheter against the stream of blood flowing out, which makes the microdialysis probe more difficult to operate and encourages damage to the probe, as a result of kinking for example. Even comparatively short microdialysis probes of a length of 10 cm for example, for use in a conventional indwelling venous catheter, can be threaded in only with a great deal of skill. Another factor that makes things more difficult is that inside cannulas and catheters there are edges at widenings and connectors on which the tip of a microdialysis probe may catch and may possibly be bent, or damaged in some other way.
Another disadvantage is that the shape of the blood-filled space within a cannula or catheter becomes less regular when there is a microdialysis probe inserted or it may even happen that dead spaces are created in which the through-flow of blood is not optimum. In such cases, there is an increase in the tendency to become clogged and possibly in that for air bubbles to collect and, overall, in the falsification of the sensor signal and in the hazard to the patient.